Junctionopathies: Disorders of the Neuromuscular Junction

Junctionopathies: Disorders of the Neuromuscular Junction

Jacques PenderisPaula Martin-Vaquero


By its very name, the “neuromuscular junction” (NMJ) describes the junction between an efferent nerve (in the context of the diseases discussed in this chapter, usually a somatic efferent nerve) and the muscle innervated by that nerve. Pathological processes that affect the NMJ are commonly referred to as “junctionopathies.”

Normal anatomy and physiology of the neuromuscular junction64, 140, 159, 163, 248, 261, 264, 279, 304

The NMJ can be subdivided into three basic components: the presynaptic membrane, the synaptic cleft, and the postsynaptic membrane in the endplate region of a skeletal muscle fiber. The NMJ is part of the acetylcholine (ACh) group of neurotransmitter systems. ACh neurotransmitter systems are also found in autonomic ganglia and parasympathetic effector junctions in the peripheral nervous system, in the spinal cord, and in the brain (particularly as a major component of the ascending reticular activating system). Each motor neuron innervates a number of muscle fibers (myofibers); combined, these are termed a motor unit. For successful NMJ transmission to occur, the action potential traveling down a motor neuron to a myofiber must be successfully propagated to the endplate region of the innervated muscle fiber. The arriving action potential at the level of the nerve terminal results in depolarization of this region and the consequent opening of calcium (Ca2+) channels on the axolemmal surface. The increased cytosolic concentration of Ca2+ triggers exocytosis of ACh by causing ACh-containing vesicles to dock and fuse with the plasmalemma at the synaptic cleft region. Three classes of proteins are involved in the process of ACh exocytosis and all three are vulnerable to toxins and disease processes:

  • synapsin I (controls the availability of synaptic vesicles) and synaptotagmin (associated with N-type Ca2+ channels)

  • synaptobrevin (vesicle-associated membrane protein), syntaxin, and synaptosome-associated protein 25, which are all essential components of the exocytosis process

  • N-ethylmaleimide-sensitive fusion protein (NSF) and soluble NSF-attachment proteins, which are all involved in neurotransmitter release.

The released ACh molecules cross the synaptic cleft to reach the ACh receptors, located on the endplate region of the skeletal muscle fiber. The ACh receptor molecules are integral membrane proteins consisting of five subunits and function as sodium (Na+) channels. The five subunits are arranged in a circular shape around the central Na+ channel (Fig. 19.1). Located on the extracellular portion of the alpha (a)-subunit (of which there are two per receptor molecule) are the ACh binding sites. Binding of ACh to the ACh binding sites results in the opening of the Na+ channel and Na+ influx into the muscle cell. This influx of Na+ results in depolarization of the endplate region, termed the endplate potential (EPP). The EPP has to reach a threshold to result in the sufficient spread of the depolarization along the muscle fiber to cause release of the intracellular Ca2+ stores and result in muscle contraction.


Figure 19.1 The ACh receptor consists of five subunits arranged in a circular shape around the central Na+ channel. The ACh binding sites are located on the extracellular portion of the two (a)-subunits. Binding of ACh to the ACh binding sites results in opening of the Na+ channel and Na+ influx into the muscle cell. (The Ohio State University. Reproduced with permission.)

The magnitude of the EPP depends on the number of ACh receptors activated. In the normal situation, there is an overabundance of both available ACh and ACh receptors and the EPP produced by nerve depolarization therefore usually far exceeds the requirement for muscle contraction; this excess is termed the safety factor of neuromuscular transmission. During repetitive depolarization of the nerve terminal following repeated firing of a motor nerve, there is a decrease in the amount of ACh released into the synaptic cleft with each depolarizing event, a phenomenon termed rundown. In normal individuals, however, the degree of rundown is insignificant due to the large safety factor of neuromuscular transmission. Following successful NMJ transmission, several processes prevent excessive stimulation of muscle fibers. First, the Na+ channels that open following activation of ACh receptors do so only transiently before closing and becoming refractory for a few seconds. Second, shortly after its release into the synaptic cleft, the ACh is rapidly eliminated by both diffusion away from the cleft region and by hydrolysis by ACh esterase (AChE) in the cleft region.

Vulnerability of the neuromuscular junction

Disorders affecting neuromuscular transmission are usually classified as pre- or postsynaptic, although some disease processes may affect both. Processes affecting neuromuscular transmission may either increase or decrease the activity of this system and do so by:

  • increasing or decreasing presynaptic ACh release, as a result of altering ACh synthesis, transport, reuptake, or presynaptic release

  • altering the concentration or duration of ACh effect in the synaptic cleft, as a result of altered removal of ACh from the synaptic cleft

  • acting as an ACh agonist or antagonist at the NMJ by affecting the interaction between ACh and the postsynaptic receptor.

Botulism toxin and α-latrotoxin (a toxin elaborated by the black widow spider) can be used as examples of diseases affecting the same component of neuromuscular transmission in opposite manners but with the same result: the failure of neuromuscular transmission. Botulism light-chain toxin (the entry of which through the plasmalemma is facilitated by the heavy-chain toxin) blocks synaptic transmission by cleaving synaptic vesicle fusion proteins required for the process of exocytosis. In contrast, α-latrotoxin causes massive ACh release at the NMJ by apparently increasing the probability of vesicle fusion with the plasmalemma and inhibiting vesicle recycling.

  1. Vulnerability of the axonal transport system

    Although not specifically disorders of the NMJ, substances may interfere with normal neuronal and axonal functions, resulting in disruption of the normal anterograde transport of material essential for neurotransmitter synthesis (including ACh at the NMJ). An example would be vincristine, which nonspecifically blocks axonal transport.

  2. Vulnerability of the presynaptic functions

    The functions within the presynaptic region are involved in the reuptake of choline from the synaptic cleft, the synthesis of ACh, and the storage thereof in synaptic vesicles, with a large number of substances and disease processes known to target these processes.

    Examples of substances affecting these pathways include:

    1. The Na+-dependent high-affinity choline transport system is specifically targeted by hemicholiniuum, which competes with choline for uptake by the choline-carrier and inhibiting choline uptake, thereby resulting in NMJ blockade.

    2. The enzyme choline acetyltransferase, involved in ACh synthesis, is targeted by a number of substances including the naphthoquinones and halogenated cholines, which have been shown to be effective enzyme inhibitors in vitro. Choline acetyltransferase is also targeted by false cholinergic neurotransmitters, including triethylcholine and diethylaminoethanol, which are acetylated by the enzyme, stored in synaptic vesicles, but on synaptic release display cholinergic agonist activity below that of ACh (cholinergic hypofunction).

    3. Vesamicol (an experimental substance) is one of a number of substances shown to induce neuromuscular blockade by blocking the transport of ACh into synaptic vesicles.

  3. Vulnerability of presynaptic release of ACh

    Numerous toxins target the presynaptic release of ACh. Botulinum toxin and certain snake toxins (including Mojave toxin and β-bungarotoxin, among others) block the release of ACh from motor axon terminals. As previously discussed, α-latrotoxin (from the black widow spider) causes NMJ blockade by targeting the same part of the system, but instead by causing massive ACh release.

  4. Vulnerability of AChE

    Numerous naturally occurring and synthetic substances target the AChE system, resulting in increased synaptic residence of ACh and therefore excessive stimulation following ACh release. Some of the substances bind to the AChE active site for varying times (including edrophonium, physostigmine, and neostigmine) while others interact with the active center to form stable complexes (e.g. organophosphorus compounds).

  5. Vulnerability of nicotinic muscle receptors

    A wide variety of compounds target the nicotinic receptors, either throughout the nervous system or specific to only the nicotinic receptors of muscle. For example, the snake toxin α-bungarotoxin (from the many-banded krait, Bungarus multicinctus) blocks the nicotinic muscle receptors, but those in peripheral autonomic ganglia appear resistant. The compounds affecting the nicotinic muscle receptors include, among others, strychnine (the indole alkaloid from the Strychnos spp.), many snake toxins, anatoxin-a from blue-green algae, and curare-like substances.

Clinical presentation of neuromuscular transmission syndromes16, 205, 264, 279, 304

NMJ transmission disorders are frequently classified as either pre- or postsynaptic. Irrespective of the cause of failure of neuromuscular transmission, the presenting clinical signs may often be very similar in character. Junctionopathies usually present as symmetric, progressive muscle weakness of both the thoracic and pelvic limbs (Fig. 19.2). Tendon reflexes are often intact in the early stages of the disease, which is a useful method to distinguish these diseases from peripheral neuropathies. The NMJ transmission syndrome frequently demonstrates a predilection for certain muscle groups, particularly the small, rapid-movement muscle groups. For this reason, failure of certain cranial nerve muscles may be apparent, including the failure of the extraocular muscles and muscles to control the palpebral reflex and alterations in the voice (dysphonia) and swallowing. Sensory function and level of consciousness are typically unaffected. In botulism, a combination of skeletal muscle weakness and autonomic nervous system dysfunction (e.g. urinary retention, alterations of heart rate, mydriasis with depressed pupillary light reflexes) is often seen, secondary to the action of the botulinum toxin blocking the release of ACh from both the NMJ and the cholinergic autonomic synapses. In some postsynaptic disorders (e.g. organophosphorus compound poisoning), there may be additional cholinergic signs, including lacrimation, miosis, and bradycardia.


Figure 19.2 Great Dane with acquired exercise intolerance demonstrating (A) exercise-induced weakness with cervical ventroflexion and respiratory distress, followed by (B) collapse into ventral recumbency.

In most cases, removal of the source of NMJ blockade will result in a rapid resolution of the clinical signs, but in some cases there is tight binding of the agent to the NMJ (e.g. botulism) and recovery may take a prolonged period of time.

Based on the classification of NMJ transmission disorders, examples of mainly presynaptic agents include: botulinum toxin, tick saliva, and black widow spider venom. Examples of postsynaptic agents include: anticholinesterase agents, tetracycline antibiotics, and interferon-a. Most of the toxic NMJ transmission disorders include a combination of both pre- and postsynaptic blockades and include: snake envenomation, aminoglycoside antibiotics, and polymyxin antibiotics.

Myasthenia gravis (MG)

  1. Congenital myasthenia gravis34, 62, 83, 84, 93, 129, 132, 133, 178, 187, 188, 205, 213, 228, 257, 300 (Video 40)

    1. Congenital MG is due to an abnormal reduction in the number of ACh receptors on the muscular endplate, resulting in clinical signs of exercise-induced weakness.

    2. The disorder has been described in a number of breeds, including Springer Spaniels, Jack Russell Terriers, Smooth-haired Fox Terriers, Samoyeds, and Miniature Dachshunds. Although reported, congenital MG is rare in cats. Clinical signs of recurrent and progressive muscle fatigue usually become apparent between 6 and 9 wks of age. Multiple pups in a litter are usually affected. In both the terrier breeds, autosomal recessive inheritance has been demonstrated. A myasthenic syndrome, inherited as an autosomal recessive disorder, has been described in the Gammel Dansk Honsehund (Old Danish pointing dog), where a presynaptic disorder interferes with ACh synthesis. A missense mutation in exon 6 causing a single-base G to A substitution in the CHAT gene, which encodes the enzyme choline acetyltransferase, has been identified in affected dogs of this Danish breed. This enzyme is involved in the resynthesis of ACh, and mutations in this gene have been associated with human myasthenic syndromes. Affected Danish dogs are homozygous for the mutation, while unaffected dogs are either homozygous for the normal allele or heterozygous carriers. A DNA test has been developed and is now available to screen Gammel Dansk Honsehunds for this mutation. In breeds other than the Gammel Dansk Honsehund and Miniature Dachshund, congenital MG is characteristically a progressive disorder, and affected dogs are often unable to walk. All breeds may be predisposed to developing aspiration pneumonia, although megaesophagus is typically demonstrable only in the Smooth-haired Fox Terrier.

    3. Due to the absence of antibodies to ACh receptors in congenital MG, diagnosis is by signalment, history, and a suitable response to anticholinesterase drugs. Ultrastructural demonstration of decreased ACh receptors in the motor endplates of fresh-frozen biopsy specimens from the external intercostal muscles may help to confirm the postsynaptic disorder (Fig. 19.3).


      Figure 19.3 Normal ACh receptor concentration in a control 4-mo-old Jack Russell Terrier (arrow) (A) and dramatically decreased ACh receptor numbers in a Jack Russell puppy affected by congenital MG (arrow) (B).

    4. Although the extent of clinical responsiveness is often incomplete and unpredictable, anticholinesterase therapy (e.g. pyridostigmine) is recommended for dogs with congenital MG. Remission of clinical disease is unlikely in most of these cases and lifelong management is therefore required. However, in Miniature Dachshunds the disease appears to resolve spontaneously by 6 mos of age. In the remainder breeds, the prognosis of congenital MG is guarded to poor due to the progressive nature of the disorder. Affected dogs may also develop recurrent or severe aspiration pneumonia.

  2. Acquired myasthenia gravis2, 5, 9-11, 15, 18, 20, 22, 23, 25, 26, 28, 34, 36, 39, 45-47, 51, 56-61, 64, 65, 68, 69, 78, 87-89, 91, 92, 94, 98, 108-110, 115, 121, 123, 127, 129, 133, 138, 140-144, 148, 151, 152, 159, 160, 163, 165, 174, 180, 181, 184, 193, 195, 196, 201-203, 205, 211, 224-226, 234, 236, 238, 242, 244, 248, 249, 255-270, 272, 277, 279-281, 287, 288, 292, 295, 296, 301, 304, 305, 309

    1. Acquired MG is an autoimmune disease in which antibodies (in most cases IgG) are formed against the nicotinic ACh receptors, resulting in decreased numbers of receptors on the postsynaptic sarcolemmal surface (Fig. 19.4). In the majority of both human and canine cases, these antibodies have been shown to recognize the same epitopes on the ACh receptor. These epitopes are primarily located in the main immunogenic region of the two alpha subunits, on the extracellular surface. The main immunogenic region is in close proximity to (although distinct from) the ACh binding site. These autoantibodies alter the receptor function by one of three mechanisms:


      Figure 19.4 Schematic representation of a normal neuromuscular junction (A) and one from a patient affected by myasthenia gravis (B). The axon terminal contains the ACh molecules within secretory vesicles, which are released into the synaptic cleft. In myasthenia gravis, the ACh receptor concentration may be reduced and there may be abnormal folding of the muscle endplate. (The Ohio State University. Reproduced with permission.)

      • Antibodies may bind directly to the ACh receptor, resulting in a blockade of ion channel opening.

      • Antibodies may increase the degradation rate of ACh receptors by cross-linkage, resulting in a decreased concentration of receptors at the postsynaptic membrane.

      • Complement-mediated lysis of the muscle endplate may take place.

         The consequence of this decrease in normal NMJ transmission is skeletal muscle weakness.

         In humans, dogs, and cats, a bimodal age of onset has been identified. Cats are typically affected between 2 and 3 yrs of age or between the ages of 9 and 10 yrs. In dogs, this bimodal age of onset occurs in young dogs between 4 mos and 4 yrs (average, 3 yrs) and in older dogs between 9 yrs and 13 yrs of age (average, 10 yrs). Acquired MG occurs much less commonly in the cat as compared to the dog. Purebred cats tend to develop MG more often than mixed-breed cats, with the Abyssinian and Somali breeds appearing to be overrepresented. In dogs, a high risk for the disease exists in several breeds, including Akitas, several terrier breeds, German Shorthaired Pointers, and Chihuahuas. The German Shepherd dog and Golden Retriever demonstrate the highest absolute morbidity. Sexually intact dogs may be slightly less likely to develop MG than spayed or neutered dogs. A group of young adult Newfoundlands from two distinct lineages with acquired MG were reported. Similarly, three young adult Great Dane littermates were reported to develop clinical signs of acquired MG over a 4-mo period. These two reports suggest that a familial and possibly genetic predisposition to acquired MG may exist in the Newfoundland and Great Dane breeds.

         Acquired MG can present in the dog and cat as one of three different clinical syndromes: focal MG, generalized MG, and acute fulminating MG. Acquired MG has been associated with other diseases and these should be taken into consideration when planning the diagnostic evaluation of a case and determining the prognosis. These include:

      • hypothyroidism

      • thymomas

      • thymic cysts

      • nonepitheliotropic cutaneous lymphoma

      • cholangiocellular carcinoma

      • anal sac adenocarcinoma

      • osteogenic sarcoma

      • oral sarcoma

      • methimazole therapy in cats

      • masticatory muscle myositis

      • dysautonomia.

         The association of thymomas and acquired MG has been demonstrated in human patients, dogs, and cats. The incidence of cranial mediastinal masses in dogs with acquired MG is low at around 3%, but this figure is considerably higher in cats (15–26%). A recent retrospective study including 116 dogs with thymoma reported that 20/116 (17%) dogs showed clinical signs consistent with MG.

    2. In MG cases, the neurologic examination is usually normal when performed prior to the induction of exercise-induced weakness; however, some cases will demonstrate depressed to absent palpebral reflexes in the absence of generalized muscle weakness. Loss of the palpebral reflex is particularly noticeable in cats. Tendon reflexes are usually normal. Clinical findings in canine- and feline-acquired MG are summarized in Table 19.1. Focal, generalized, and acute fulminating forms of MG have been described in dogs and cats. Focal MG presents as weakness of isolated muscle groups, particularly the esophageal, pharyngeal, laryngeal, and facial muscles. Weakness of these muscle groups occurs in the absence of generalized appendicular muscle weakness. The main presenting clinical signs in these cases include:

      Table 19.1 Clinical findings in cats and dogs with acquired MG.

      Cats Cats Dogs Dogs
      Clinical findings (%) (n +20) (%) (n +25)
      Generalized weakness 70 14 64 16
      Decreased palpebral reflex 60 12 36  9
      Decreased menace response 50 10
      Decreased gag reflex 32 8
      Laryngeal weakness 24 6
      Megaesophagus 40 8 84 21
      Aspiration pneumonia 20 4 84 21
      Cranial mediastinal mass 15 3 8 2
      Muscle fasciculations 15 3
      Decreased flexor reflexes 10 2
      Polymyositis 5 1 8 2
      Cardiomegaly 5 1
      Muscle atrophy 5 1

      Source: Adapted from Dewey CW, Bailey CS, Shelton GD, et al. Clinical forms of acquired myasthenia gravis in dogs: 25 cases (1988–1995). J Vet Intern Med. 1997;11:50–57; and Ducoté JM, Dewey CW, Coates JR, Clinical forms of acquired myasthenia gravis in cats. Compend Contin Educ Pract Vet. 1999;21:440–448, with permission.

      • regurgitation secondary to megaesophagus

      • dysphagia due to pharyngeal muscle weakness

      • dropped jaw

      • diminished or absent palpebral reflexes

      • voice changes (dysphonia) due to laryngeal and/or palatal muscle weakness.

         In retrospective studies, 36–43% of dogs presenting with acquired MG demonstrated focal signs, compared to only 15% of cats. These focal signs were mostly secondary to the presence of megaesophagus and dysphagia. The differences in the prevalence of focal signs between both species may be ascribed partially to the larger proportion of smooth muscle in the feline esophagus as compared to the predominantly striated muscle of the canine esophagus.

         The generalized form of MG is characterized by appendicular muscle weakness that may be induced or exacerbated by exercise. Retrospective studies reported that generalized weakness with or without megaesophagus was present in 57–64% of dogs and 80% of cats with MG. Typically, severe exercise intolerance develops after only a few minutes of exercise, but following rest the animal regains muscle strength and can return to activity for a short period before a relapse of the muscular weakness. Regurgitation, especially in dogs, may occur secondary to either megaesophagus or a thymic mass. Muscle tremors and decrementing or absent palpebral reflexes may be present as a feature of the muscle weakness. Pharyngeal and laryngeal muscle weakness is evidenced by the presence of excessive drooling, a moist and productive cough (secondary to aspiration pneumonia), and dysphonia. Appendicular muscle weakness tends to be more severe in the pelvic limbs of dogs, whereas this has not been reported in cats. Cats may frequently demonstrate cervical ventroflexion as a clinical sign of generalized weakness; in some cases, such cats may prefer to remain in thoracic recumbency with their heads supported on their thoracic limbs (Fig. 19.5). Generalized MG has been associated with polymyositis in one cat. Third-degree atrioventricular block has been reported to occur concurrently with MG in dogs. Cardiac involvement in MG is well documented in human medicine and may be the result of autoantibodies directed against the conducting tissue of the heart, or as a result of secondary focal myocarditis.


      Figure 19.5 (A) Cats with weakness secondary to acquired myasthenia gravis may demonstrate cervical ventroflexion as a sign of generalized weakness. (B) Affected cats may also show a preference to remain in thoracic recumbency with their heads supported on their thoracic limbs. (Dr. Andrew Sparkes, Animal Health Trust, UK, 2014. Reproduced with permission from Dr. Andrew Sparkes.)

         Acute fulminating MG is a severe and rapidly progressing form of generalized MG. Affected animals demonstrate regurgitation secondary to megaesophagus and a rapid progression of appendicular muscle weakness, which usually renders the dog nonambulatory. Weakness of the skeletal muscles eventually affects the intercostal muscles and/or diaphragm, at which stage affected animals demonstrate severe respiratory distress. Due to the concurrent pharyngeal and laryngeal muscle weakness, aspiration pneumonia is a frequent complication. It is not uncommon for dogs with fulminating MG to also have concurrent thymomas. The prognosis for fulminating MG is poor. For successful treatment, these cases require rapid recognition and intensive care, including respiratory supportive care, and possibly plasmapheresis.

    3. Disorders that may mimic MG include other disorders of the NMJ as well as diseases presenting with generalized or focal weakness of striated muscle. The most important differential diagnoses to consider include:

      • other disorders of the NMJ, in particular botulism, snake envenomation, tick paralysis, and cholinesterase toxicity

      • neuropathies and myopathies (particularly inflammatory and breed-related myopathies).

         The diagnostic approach to the MG case is challenging, as historical and clinical signs of dysfunction may be caused by a variety of other diseases, including diseases of the peripheral nervous system, NMJ, and muscle. Some of the tests for MG are supportive but not diagnostic, while others may require general anesthesia. The clinician needs to be aware of the limitations of the available tests in order to make a diagnosis as quickly as possible without detriment to the patient.

      1. Minimum database

        In every patient presenting with clinical signs of suspected MG, a minimum database—including a complete blood count, biochemistry panel, and urinalysis—should be performed to rule out other causes of generalized or focal weakness. Additionally, problems might be identified on the minimum data base that require intervention, particularly in animals demonstrating dysphagia or megaesophagus who may have complications secondary to compromised fluid or nutritional intake. Further endocrine testing, particularly of thyroid and adrenal function, may be indicated based on the presenting clinical signs and findings on the minimum database. Although myopathies are one of the most important differential diagnoses for MG, care must be taken when interpreting muscle enzyme levels, particularly in animals that have been recumbent for a prolonged length of time; recumbency and mild to moderate muscle damage (e.g. an intramuscular injection, falling down) may result in moderate elevations of the creatine kinase (CK) level in the absence of substantial muscle damage.

      2. Imaging studies

        Thoracic radiographs should be obtained to evaluate for the presence of megaesophagus (preferably unsedated, as both sedation and anesthesia can induce an apparent megaesophagus in normal animals). Megaesophagus is a frequent finding in dogs with MG and is often associated with the presence of aspiration pneumonia (Fig. 19.6). In cats, megaesophagus is less common, but its presence may indicate a more guarded prognosis. In cases with a historical suggestion of megaesophagus, for which there is no evidence on thoracic radiographs, esophagography with liquid barium and fluoroscopy has been suggested. However, MG patients with poor pharyngeal and esophageal function are at a greater risk of aspiration pneumonia, and the aspiration of barium could dramatically exacerbate aspiration pneumonia. A safer alternative to a barium esophagram is esophageal scintigraphy. Esophageal scintigraphy is safe and easily performed; this procedure also provides objective information pertaining to esophageal function.


        Figure 19.6 Lateral thoracic radiograph demonstrating megaesophagus in a dog with evidence of secondary aspiration pneumonia (Dr. P Scrivani, Cornell University, 2014. Reproduced with permission from Dr. P Scrivani.)

           Thymoma has been associated with acquired MG in human, canine, and feline patients. The presence or absence of a cranial mediastinal mass should therefore be assessed with radiography (and ultrasonography if indicated). Such masses are only occasionally present (3.4%, in one study) in canine patients with acquired MG (Fig. 19.7). In feline-acquired MG, however, the incidence of a cranial mediastinal mass has been reported to be between 15 and 25.7%. The absence of a radiographically demonstrable cranial mediastinal mass does not rule out the possibility of a thymoma. Further imaging, including computed tomography and magnetic resonance imaging, is often helpful in human medicine to evaluate the anterior mediastinum.


        Figure 19.7 Lateral thoracic radiograph of a dog with MG demonstrating a large cranial mediastinal mass (thymoma) and megaesophagus. (Dr. P Scrivani, Cornell University, 2014. Reproduced with permission from Dr. P Scrivani.)

           An ECG should be performed (particularly if bradycardia is present) to rule out third-degree heart block.

      3. Edrophonium chloride challenge (Tensilon response) test

        To support the presumptive diagnosis of MG, an edrophonium chloride challenge test can be performed in animals demonstrating muscular weakness. Edrophonium chloride is an ultrashort-acting anticholinesterase agent, prolonging the residence time of ACh in the synaptic cleft and thereby improving muscle strength where NMJ blockade is present. A positive response to an intravenous injection of edrophonium chloride is supportive of a presumptive diagnosis of MG. An intravenous catheter is placed prior to the challenge test. In dogs, 0.1–0.2 mg/kg is administered intravenously immediately after exercise-induced weakness. In cats demonstrating muscular weakness, a dose of 0.25–0.50 mg per cat is administered intravenously, after which the patient is observed for evidence of increased muscular activity. A positive response is one in which there is a dramatic increase in muscle strength; this improvement is usually maintained for only a few minutes.

           Although edrophonium chloride is relatively safe as a diagnostic agent (due to its short duration of action), atropine should still be available in case a cholinergic crisis is induced. The disadvantages of using edrophonium chloride are primarily the possibility of both false-positive and negative results, and this test is therefore only used as a guide to revealing the presence of MG. Other disorders causing NMJ block may also demonstrate a partial response to edrophonium chloride, while in those MG patients with insufficient available ACh receptors, an inapparent or small response may be evident, despite prolonging the residence time of the ACh. The results of the test are also subjective and depend on the assessment and interpretation of the examiner.

           In focal MG, particularly in cats, there is often no detectable improvement in muscular strength and the test is of little use. An exception to this would be a focal MG case with a decremental palpebral response. Such patients often demonstrate an improvement in the palpebral response following edrophonium administration. The short-acting properties of edrophonium chloride, which make it a safe and suitable diagnostic tool, may also make it unsuitable in those cases that either have very brief collapse episodes or are difficult to administer intravenous agents to during a collapse episode. In these cases the use of a longer-acting anticholinesterase agent, neostigmine, would be indicated and following administration the animal exercised to see whether the weakness episodes can be abolished or improved. Due to the long-acting nature of neostigmine, prior administration of atropine is recommended to prevent a cholinergic crisis. The main risk during the administration of any anticholinesterase agent is that of inducing a cholinergic crisis. Overstimulation of muscarinic ACh receptors can result in adverse side effects, including bronchoconstriction and bradycardia. These can be prevented by pretreatment with antimuscarinic agents, either SC or IM atropine (at 0.02–0.04 mg/kg) or glycopyrrolate (at 0.01–0.02 mg/kg). Overstimulation of nicotinic ACh receptors can induce a depolarizing blockade and exacerbate muscular weakness. The clinician should therefore be ready to provide respiratory support in rare cases in which respiratory paralysis occurs.

      4. Electrodiagnostic assessment

        Electrodiagnostic assessment is often useful in the diagnosis of MG, but is limited by the availability of the equipment and the requirement for generalized anesthesia (which may be contraindicated in cases with respiratory impairment due to muscular weakness or aspiration pneumonia).

      5. Repetitive nerve stimulation

        The repetitive nerve stimulation test utilizes the area or amplitude of successive compound muscle action potentials (CMAP) obtained by repetitively stimulating the nerve supplying that muscle. The tibial, peroneal, or ulnar nerves are usually utilized, with the recording electrodes placed in the digit innervated by that particular nerve. In the normal animal, the amplitude should remain constant at stimulation rates of 5 Hz or less. A decremental response to repetitive nerve stimulation at a stimulation rate of 5 Hz or less is supportive of a diagnosis of MG (Fig. 19.8). A decrease in the compound muscle action potential of 10% or more is considered abnormal. At higher stimulation rates, normal animals will often demonstrate a decremental response. The test is highly sensitive for MG in human patients, although the test is more likely to yield a positive response in cases with generalized MG than focal MG. Repetitive nerve stimulation in focal MG is still more sensitive than determining serum ACh receptor antibody concentrations in human cases with focal MG. Some other NMJ disorders (e.g. organophosphate toxicity) may also demonstrate a decremental response.


        Figure 19.8 Repetitive nerve stimulation in a Jack Russell Terrier with congenital myasthenia gravis, demonstrating progressive decrement of the compound muscle action potential. Normal animals would not demonstrate decrement at stimulation rates less than 5 Hz.

      6. Single-fiber electromyography (SF-EMG)

        A more specific test for NMJ blockade induced by MG, in both dogs and humans, is single-fiber electromyography. The use of SF-EMG is limited at present due to the availability and cost of the recording needles, as well as the expertise required to perform the test. SF-EMG is based on obtaining recordings of the evoked action potential from single muscle fibers using a special recording needle with a very small recording surface. This is in contrast to the conventional recording needles that record motor unit action potentials, which represent the synchronous depolarization of many adjacent muscle fibers. Based on the recording of the evoked action potential from one muscle fiber, the time variation in neuromuscular transmission for that fiber (jitter) can be determined. The test is based on the fact that the time variation for neuromuscular transmission (or latency from stimulus to action potential) is virtually constant for that muscle fiber with repeated measurements. Any alteration in NMJ transmission is likely to result in an increased variation in the time of NMJ transmission. The test can be performed by one of two methods:

        1. The latency from the time of stimulus to the peak of an action potential for a single muscle fiber can be recorded repeatedly. The jitter value is then calculated by determining the mean value of the consecutive differences in latency (Fig. 19.9). In normal patients the latency is virtually constant.


          Figure 19.9 Single fiber electromyography from a normal (A) and myasthenic (B) patient illustrating the increased variation in latency (jitter) occurring with MG. (The Ohio State University. Reproduced with permission.)

        2. The interval between the evoked action potentials for two different muscle fibers from the same motor unit (interposital latency) can be measured repeatedly. The jitter value is the mean value of the consecutive differences in interposital latency.

           The test is not specific for MG as any disorder of NMJ transmission may result in an abnormal jitter result. However, the main contribution to jitter is impulse conduction at the synaptic cleft-endplate region of the NMJ. In human MG, SF-EMG is considered the most sensitive test for diagnosing all forms of MG, with 92–100% of myasthenic patients demonstrating abnormal jitter values. A method for determining jitter has been reported in dogs, but use of the test in the diagnosis of MG has not been reported in veterinary practice to date.

      7. Demonstration of elevated anti-ACh receptor antibody concentrations

        The definitive diagnosis for acquired MG is made by demonstrating circulating antibodies directed against nicotinic ACh receptors of skeletal muscle, with the highest antibody concentrations generally occurring in cases with acute fulminating MG. Congenital MG will have a negative antibody concentration. The test is an immunoprecipitation radioimmunoassay using 125I α-bungarotoxin-labeled ACh receptors. In the canine test, the ACh receptors are obtained from near-term fetal canine muscle. The test is available for dogs and cats at the Comparative Neuromuscular Laboratory, University of California, San Diego (vetneuromuscular.ucsd.edu). There appears to be some cross-reactivity in antibody recognition of the ACh receptors between species, but the assay is relatively species-specific, and a canine- or feline-specific assay system should be used. An ACh receptor antibody concentration of greater than 0.30 nmol/L is positive for acquired MG in cats, while greater than 0.6 nmol/L is positive in dogs. False-positive tests are extremely rare and a positive result is therefore virtually confirmatory for a diagnosis of acquired MG. The test is performed on a serum sample and is relatively inexpensive. The serum ACh receptor antibody concentration is usually lowest in cases with focal MG and highest in cases with acute fulminating MG. Within an individual, ACh receptor antibody concentrations seem to correlate well with the disease severity. However, antibody concentrations between patients are highly variable, and do not correlate well with severity and/or degree of weakness.

           In human MG, the immunoprecipitation radioimmunoassay fails to detect 10 to 15% of generalized MG cases and 30 to 50% of focal MG cases, with these patients being referred to as seronegative myasthenics. There is evidence that this situation also occurs in canine patients with acquired MG. Approximately 2% of dogs with generalized MG are seronegative. The percentage of seronegative dogs with focal MG is not currently known. The proposed reasons for the failure of this technique to detect some cases include:

        • In some cases, the affinity of the antibody is such that all of the available antibody is bound to the muscle endplate region with undetectable levels of circulating antibody.

        • During solubilization of the ACh receptors for the test probe, damage to certain antigenic epitopes of the ACh receptor may occur and the test probe may therefore fail to recognize some antigenic variations of the ACh receptor antibodies.

        • Some of the antibodies in acquired MG may be directed against antigenic proteins of the endplate region other than the ACh receptors (autoantibodies against non-ACh skeletal muscle proteins, such as titin and ryanodine receptor), and these would therefore not be identified by the test. In dogs, MG has been associated with autoantibodies against skeletal muscle striations and ryanodine receptors in dogs with thymoma, and against titin in older-onset MG.

        • Immunosuppressive therapy for longer than 7–10 days will lower antibody titers, so the use of a pretreatment blood sample is strongly recommended.

           Criteria used to classify dogs as having seronegative MG include:

        1. clinical signs consistent with MG

        2. consistent pharmacologic response (positive edrophonium test) and electrophysiologic findings (decremental response of CMAP during repetitive nerve stimulation)

        3. normalization of appendicular muscle weakness following acetylcholinesterase therapy with neostigmine or pyridostigmine

        4. at least two negative serum ACh receptor antibody titers as determined by immunoprecipitation radioimmunoassay.

      8. Demonstration of immunoglobulin localized to the endplate region of muscle

        Supportive of the diagnosis (but not specific for acquired MG), immune complexes may be demonstrated at the level of the NMJ by immunocytochemistry of fresh muscle biopsy specimens or by incubating the patient’s serum with stored normal canine muscle samples. The test is relatively inexpensive and easy to perform, but the staphylococcal protein A-horseradish peroxidase conjugate is not specific to antibodies against the ACh receptors; the test is therefore not specific for acquired MG. The test is, however, a useful screening tool, as a negative result generally rules out the possibility of acquired MG. Pretreatment with immunosuppressive drugs may decrease the chance of a positive test.

    4. Treatment of MG can be subdivided into supportive treatment, which is similar for all cases with neuromuscular blockade, and specific therapy, aimed at relieving the NMJ blockade and controlling the underlying autoimmune process in acquired MG.

      1. Supportive treatment

        1. Aspiration pneumonia

          Prevention and/or treatment of aspiration pneumonia are/is important due to the increased morbidity and mortality associated with its development. Recumbent patients should be turned frequently (every 2–4 hrs) to prevent hypostatic lung edema and exacerbation of any existing pneumonia. If aspiration pneumonia is present, or the development thereof is thought to be likely, antibiotic therapy should be implemented. Ideally, the choice of antibiotic should be based on culture and sensitivity results from tracheal wash fluid and should be tailored to avoid using antibiotics associated with NMJ blockade (see “Antibiotics” section below). Frequent nebulization and coupage are useful in the treatment of pneumonia.

        2. Fluid requirements

          The maintenance of hydration in the face of significant regurgitation can be a challenge, especially as some animals tend to regurgitate liquids more readily than solids. Maintenance of fluid requirements with intravenous fluid therapy should be initiated if required.

        3. Nutritional support

          Maintenance of dietary intake is important in recumbent patients and particularly those with dysphagia or regurgitation. Elevated feeding may help in some cases with megaesophagus, but maintaining head elevation is difficult in cats. In dogs, a specially designed feeding chair can be used, such as the “Bailey chair” (Fig. 19.10). This type of feeding chair allows for the dog to sit in an upright position for feedings. Ideally, the dog should sit in the upright position for 10–15 min after feedings to allow the food to move into the stomach, which decreases the risk of aspiration pneumonia in myasthenic dogs with megaesophagus. In those patients in which elevated feeding is undertaken, determining the ideal food consistency for that individual case is a matter of trial and error. Solid food stimulates pharyngeal and esophageal peristalsis more effectively in the normal dog, but some dogs with pharyngeal and esophageal dysfunction tolerate semisolid food better. The head should be maintained elevated throughout feeding and for 10 to 15 min following feeding. In those cases with unmanageable regurgitation, a nasogastric, esophageal, or, ideally, a gastrostomy tube can be placed. Due to poor esophageal function, regurgitation can still occur with a nasogastric or esophageal tube, and a gastrostomy tube would be better suited to MG patients. The advantages of gastrostomy tube placement include that head elevation during feeding is no longer required, the risk of aspiration pneumonia is reduced, and proper delivery of oral medication can be guaranteed (versus variable delivery and passage time with megaesophagus and dysphagia). The disadvantages of gastrostomy tube placement are that only semiliquid and liquid foods can be administered and tube placement requires a short general anesthetic that may be deleterious to some myasthenic patients.


          Figure 19.10 Myasthenic dog sitting in a specifically designed feeding chair (“Bailey chair”). (Susan Sanchez, 2014. Reproduced with permission from Susan Sanchez.)

        4. Respiratory support

          Intensive care and specifically respiratory support with intermittent positive pressure ventilation may be required in animals demonstrating severe weakness.

        5. Drugs to modify gastrointestinal tract function

          The main consideration in the manipulation of gastrointestinal tract (GIT) function in MG is the management of megaesophagus and dysphagia, with the resultant complications of regurgitation, esophagitis, and aspiration pneumonia.

          1. Improving esophageal motility

            Drugs with prokinetic effects on GIT smooth muscle include metoclopramide and cisapride. Both of these drugs are believed to mediate their prokinetic effect by stimulating enteric cholinergic neurons, which in turn leads to ACh release and resultant smooth-muscle contraction. There is, however, no evidence that either of these two drugs stimulates increased esophageal motility in either the normal or MG-affected canine esophagus. Cisapride has actually been demonstrated to increase esophageal transit time in the normal dog. The dose of metoclopramide in the dog is 0.2–0.5 mg/kg given orally, intramuscularly, or subcutaneously every 8 hrs and that of cisapride is 0.1–0.5 mg/kg given orally every 8 hrs.

          2. Increasing lower esophageal sphincter tone

            Where elevated oral feeding is being used, drugs that increase lower esophageal tone should be avoided as this would result in resistance to the passage of food into the stomach. Increased lower esophageal tone would be beneficial where feeding is being performed via a gastrostomy tube by decreasing gastroesophageal reflux and consequently reducing or limiting esophagitis. Both metoclopramide and cisapride increase lower esophageal tone, with cisapride having the more potent action.

          3. Prevention and management of esophagitis

            Animals with megaesophagus and gastric reflux into the esophagus are at risk of developing esophagitis, which may in itself perpetuate esophageal dilation. The risk of esophagitis (or management thereof where esophagitis is already present) can be decreased by feeding via a gastrostomy tube (combined with drugs to increase lower esophageal sphincter resistance) and by increasing the pH of GIT content.

          4. Increasing the pH of GIT content

            The acidity of aspirated material is a major determinant of the degree of pulmonary damage in aspiration pneumonia as well as contributing to the severity of esophagitis. A frequent component of aspirated material in MG is refluxed gastric content; increasing the gastric content pH is therefore advisable in MG cases at risk of aspiration pneumonia. Famotidine is a histamine-2 receptor antagonist that increases gastric content pH. Famotidine is administered at 0.5–1 mg/kg every 12–24 hrs (orally or intravenously). Omeprazole and pantoprazole are proton pump inhibitors that also increase gastric content pH. The recommended dose of oral omeprazole is 0.7–1 mg/kg every 24 hrs. The same dose applies to pantoprazole but is administered intravenously. Overall, proton pump inhibitors appear to provide superior gastric acid suppression than famotidine.

      2. Specific therapy

        The mainstay of specific therapy in MG is the use of anticholinesterase agents, although an attempt should also be made to address the underlying disease process by immunomodulatory therapy and addressing any contributory disease processes.

        1. Anticholinesterase therapy

          Anticholinesterase drugs prolong the availability of ACh for binding to ACh receptors by inhibiting degradation by AChE. Pyridostigmine bromide is administered orally every 8 to 12 hrs at a dose of 0.5–3.0 mg/kg in dogs and 0.25 mg/kg in cats. Pyridostigmine bromide is available in both tablet and syrup forms. A slow-release tablet form is available but the gastrointestinal absorption may be erratic. Cats are more sensitive than dogs to anticholinesterase drugs; the starting dose is therefore lower than in dogs. Care should also be taken when altering the dose in cats. The dose should be started at the lower end of the scale and slowly titrated to achieve the best clinical response while avoiding cholinergic side effects. Cholinergic signs include hypersalivation, vomiting, diarrhea, and muscle fasciculations. Should these signs develop, the dose should be decreased.

             If oral medication cannot be tolerated due to pharyngeal weakness or aspiration pneumonia, then either administration of pyridostigmine by gastrostomy tube (if one has been placed), administration of pyridostigmine bromide as a constant rate infusion (0.01–0.03 mg/kg/hr), or parenteral neostigmine may be considered until oral pyridostigmine administration can be tolerated. The onset of effect for parenteral neostigmine is more rapid, but of shorter duration than pyridostigmine; it therefore needs to be administered every 6 hrs. In dogs it can be administered at a dose of 0.04 mg/kg.

             There is some variability in the response to anticholinesterase therapy, and the reason for this variability is poorly understood. Certainly, in human patients with acquired MG, most cases are not satisfactorily controlled with anticholinesterase therapy alone and these drugs are often ineffective in controlling the ocular form of the disease. Some dogs appear to respond well to therapy, while others respond poorly. To some extent, the variability in the severity of the autoimmune response against the ACh receptors may explain the variability to anticholinesterase therapy, as anticholinesterase therapy does not address the underlying autoimmune process. The effect of anticholinesterase therapy on improving esophageal function in dogs with megaesophagus is thought to be less than the effect on appendicular muscle weakness. Although myasthenic cats can be treated successfully with anticholinesterase drugs, it has been suggested that cats with MG may respond better to immunosuppression than to anticholinesterase therapy.

        2. Immunosuppressive therapy

          The use of immunosuppressive therapy in acquired MG is based on the underlying pathophysiology, an autoimmune destruction of functional ACh receptors. If an optimal response to therapy is not obtained with supportive care and anticholinesterase drugs alone, immunosuppressive therapy may be considered. There is, however, some controversy about the use of immunosuppressive therapy in MG, with the main reasons being the high incidence of aspiration pneumonia in MG (especially in canine patients) with the potential for immunosuppressive therapy to exacerbate that, as well as the potential for glucocorticoid therapy to worsen neuromuscular weakness.

        3. Glucocorticoid therapy

          The potential for glucocorticoid therapy to exacerbate muscular weakness has been demonstrated in both dogs and cats, especially in cases with marked muscular weakness and respiratory distress. However, myasthenic cats appear to be more resistant than dogs to the development of weakness associated with glucocorticoid therapy. Increased muscle weakness associated with glucocorticoid therapy has been observed in 50% of human MG patients. In cases responsive to edrophonium chloride, a conservative treatment regime would be to start pyridostigmine bromide therapy, combined with alternate-day low-dose (anti-inflammatory dose) prednisone therapy. Increasing (or in naive cases introducing) corticosteroid therapy should be considered if the response to anticholinesterase therapy is suboptimal or if the animal is demonstrating resistance to the drug therapy. An initial dosage of 0.5 mg/kg every 12 hrs is suggested in these cases, as higher doses may result in the exacerbation of neuromuscular weakness. In cats, prednisone doses of 1–2 mg/kg/day have been used and dexamethasone at 0.25–1.0 mg/kg/day. Dexamethasone is associated with more gastrointestinal side effects and a higher myopathic potential than prednisone, and its use should therefore be avoided in MG. The exact mechanism whereby prednisone results in improvement of the clinical signs of MG is not fully understood, but may be related to the inhibitory effects of prednisone on the formation and release of inflammatory agents, lymphocyte division, lymphocyte reactivity to ACh receptors, and leukocyte chemotaxis.

          1. Azathioprine

            Azathioprine is a cytotoxic antimetabolite that interferes with DNA synthesis, with its beneficial effect in acquired MG probably being mediated through reducing lymphocyte numbers and consequently immunoglobulin production, as well as specifically inhibiting T-cell production. The use of azathioprine alone or combined with prednisone has been demonstrated to be highly effective in resolving clinical signs in human MG. The potential side effects of azathioprine therapy include the development of bone marrow suppression and, less often, hepatotoxicity, pancreatitis, and GIT irritation. Bone marrow suppression is much more common in cats; azathioprine use is therefore not advised in this species.

               In dogs with evidence of bone marrow suppression (leukopenia with or without anemia and thrombocytopenia), azathioprine therapy should be discontinued (or reduced in cases with mild bone marrow suppression). It is recommended that azathioprine be discontinued if the patient’s white blood cell count is less than 4000 cells/mL, and/or if the neutrophil count is below 1000 cells/mL. The onset of the clinical effect of azathioprine is delayed in both human and canine cases. A complete immune response to this medication may take up to 6 wks, but in many cases clinical response is seen within 2 wks. Therefore, its use should be combined with prednisone if an early effect is required. A conservative prednisone dose should be used initially, as discussed earlier. The clinical signs should abate rapidly with prednisone therapy. After 2–4–mos, the prednisone therapy can be tapered to a minimum alternate-day dosage or in some cases stopped entirely. This protocol should minimize side effects with a rapid and sustained control of the clinical signs in many patients. In stable MG dogs, azathioprine may be considered as a sole immunosuppressive agent. It may take several weeks before an obvious clinical benefit is realized in such patients. The dose of azathioprine in dogs is 1–2 mg/kg once a day or every other day. Bone marrow function should be monitored by assessing for suppression on a hemogram every 1–2 wks during the initial 1–2 mos of therapy and every 1–2 mos thereafter.

          2. Cyclosporine

            Cyclosporine has been demonstrated to have some efficacy in human cases of acquired MG, and it is particularly used in those cases that cannot tolerate or are nonresponsive to other immunosuppressive drugs. Cyclosporine blocks the transcription of genes required for T-cell activation, notably those encoding immunoregulatory cytokines including interleukin-2. The dose is 3–6 mg/kg twice a day orally or intravenously. In one report, cyclosporine was successful in the treatment of two dogs with acquired MG, at a dosage of 4 mg/kg every 12 hrs. Although its specificity for lymphocytes is an attractive feature, cyclosporine can become cost prohibitive for large-sized dogs. The most common side effects in dogs include mild gastrointestinal signs, which are often transient or responsive to dose reduction. Other less common but more serious side effects include gingival hyperplasia, opportunistic infections, hepatotoxicity, allergic reactions, and lymphoproliferative disorders.

          3. Mycophenolate mofetil (MMF)

            MMF is an inhibitor of purine synthesis in both T- and B-lymphocytes. As a consequence, MMF interferes with lymphocyte proliferation, differentiation of Tc cells, and antibody responses. MMF is commonly used in people to prevent renal allograft rejection, and it has also been used to treat various autoimmune diseases (including MG). In dogs, controversial results exist about the efficacy of MMF to treat acquired MG. A case series of three dogs with severe generalized MG treated with intravenous MMF demonstrated clinical remission in 48 hrs with no adverse effects. Successful treatment of MG in a dog with oral MMF has been reported. The institution of MMF therapy resulted in a rapid resolution of clinical signs (within the first week of therapy) and the return of the ACh receptor antibody concentration to within the normal range. However, a retrospective case series including 27 dogs with acquired MG that were treated with a combination of MMF and pyridostigmine compared with those treated with pyridostigmine alone did not show any significant benefit of MMF over the long term. The recommended oral (or gastrostomy tube) dose of MMF is 7–20 mg/kg every 12 hrs. The intravenous dose of MMF is 15–20 mg/kg, diluted in 500 mL of 0.45% NaCl and 2.5% dextrose and administered over 4 hrs. The side effects of MMF described in dogs are primarily gastrointestinal (e.g. vomiting, bloody diarrhea). It is recommended that the MMF dose be reduced by half, once clinical signs of MG improve substantially or resolve, in order to minimize adverse side effects. Since side effects are typically evident by 3–4 wks of therapy with MMF, reducing the dose prior to this time is recommended, especially if a positive clinical response has already been achieved.

          4. Leflunomide and cyclophosphamide

            Leflunomide inhibits T- and B-cell proliferation, suppresses immunoglobulin production, and interferes with cell adhesion. It has been used in dogs to treat immune-mediated diseases such as immune-mediated polyarthritis, nonsuppurative encephalitis/meningomyelitis, and Evans syndrome. Leflunomide prevented the development of experimental MG in rats. There is no available information on the treatment of MG in dogs or cats.

               Cyclophosphamide is a cytotoxic alkylating agent that cross-links DNA, disrupting nucleic acid function and inhibiting cell proliferation. It has been used in people with refractory MG. Serious adverse effects can be seen with its use, including myelosuppression and hemorrhagic cystitis. There is no well-documented use of cyclophosphamide in veterinary patients with MG.

        4. Intravenous immunoglobulin (IVIg) and plasmapheresis

          Both intravenous immunoglobulin and plasmapheresis (plasma exchange) therapy have been used to treat human-acquired MG. However, reports on the efficacy of these treatments in human-acquired MG have been variable. It appears that their main value may be in the treatment of acute fulminating MG, where rapid improvement in the clinical signs is required. These techniques are limited in veterinary medicine due to the cost limitations and equipment requirements, but may be of benefit in the management of acute fulminating MG.

             The mode of action of IVIg is poorly understood but may be related to the binding of circulating autoantibodies, blocking macrophage and lymphocyte Fc receptors, enhanced suppressor T-cell activity, and inhibition of the complement cascade. A recent meta-analysis investigated the data available on the efficacy of IVIg for treating human MG. It was concluded that in MG acute exacerbations one dose of IVIg was more efficacious than placebo, with the results being borderline significant (P = 0.055). No significant difference was identified between the use of IVIg and oral methylprednisolone in the treatment of acute exacerbation of MG. In the case of chronic MG, there was insufficient evidence to determine whether IVIg was efficacious. Two dogs with MG were treated with human IVIg. The dogs received one and four IVIg transfusions each, at a dose of 0.5 g/kg. Both dogs reportedly improved with all weakness resolving within 48 hrs; however, both dogs had recurrence of clinical signs during the subsequent days to weeks. No additional veterinary studies exist evaluating the use of human IVIg in MG.

             Plasmapheresis involves removing the plasma and plasma constituents (including immunoglobulins) from the whole blood of patients and returning the blood elements with either stored plasma or plasma substitutes to the patients. Immunoadsorption therapy is a form of plasmapheresis in which a patient’s plasma is returned after being passed through a filter that adsorbs immunoglobulins. Plasmapheresis results in the removal of ACh receptor antibodies from circulation. Plasmapheresis and human IVIg have been of equal benefit in the treatment of human MG patients. Although there are reports of plasmapheresis being effective in the treatment of human MG, a recent meta-analysis concluded that the current evidence available is insufficient to support or refute the use of plasmapheresis for the treatment of human-acquired MG. A case report documented clinical remission in one dog with acquired MG who received two treatments of plasmapheresis in combination with prednisone therapy.

        5. Therapeutic vaccines

          Peptides that mimic antigen receptors of T and B cells necessary for the generation and maintenance of the autoimmune response in acquired MG have been evaluated as therapeutic vaccines in both a rat model and naturally occurring canine-acquired MG. These peptides lead to the production of anergizing antibodies against ACh-specific receptors on these immune cells, blunting the autoimmune response. Although the data are preliminary, this approach appears to be have been effective in a small number of dogs (10) evaluated. These 10 vaccinated dogs experienced a higher rate and shorter time to clinical and serologic remission when compared with historical controls.

      3. Management of concurrent neoplasia

        If a concurrent thymic mass or other neoplasia is present, surgery (with or without radiation therapy) should be considered. In humans, pathological alterations of the thymus (either thymic hyperplasia or thymoma) are present in approximately 80% of cases with generalized acquired MG showing autoantibodies against ACh receptor. The removal of thymic hyperplasia has been demonstrated to improve remission rates in human patients with acquired MG. In contrast to the removal of thymic hyperplasia, thymoma removal in human patients with acquired MG is usually not associated with an improvement in clinical signs. Occasionally, a myasthenic person will worsen following thymoma removal. An acute onset of clinical signs consistent with acquired MG following thymectomy has also been documented in dogs and cats. The improvement documented in human cases with thymic hyperplasia is probably related to the removal of a source of continued antigenic stimulation, while the worsening of the clinical signs occasionally seen in acquired MG following thymoma removal may be related to the loss of an immunosuppressive effect of the thymus.

           The beneficial effect of thymic removal in the absence of a thymoma has not been demonstrated in dogs and cats. Thymic hyperplasia has also not been described in dogs and cats with MG, and thymectomy in the absence of a demonstrable thymic mass would not be recommended, owing to the detrimental and stressful effects of surgery and anesthesia. In the few documented cases in which thymectomy was performed in dogs with acquired MG, the outcome was generally poor, particularly in those cases presenting concurrent megaesophagus, with the majority dying of aspiration pneumonia shortly after surgery. The successful management of thymoma with radiation therapy has been reported in dogs.

    5. Treatment of acute fulminating myasthenia gravis

      The mortality associated with MG is highest with the fulminating form, although luckily this is the most uncommon form of the disease. Cases present with rapidly progressive generalized weakness with concurrent megaesophagus. Rapid diagnosis and treatment (combining anticholinesterase therapy and ventilatory support) are therefore essential. The main cause of death in these cases is respiratory failure secondary to muscular weakness, and this may be further complicated by aspiration pneumonia. Care should be taken when initiating immunosuppressive therapy with corticosteroids, owing to the potential to exacerbate the muscular weakness. In human cases with acute fulminating MG, plasmapheresis and intravenous immunoglobulin have been used, but their use in veterinary medicine is limited by cost and availability.

    6. Contraindications

      Drugs that adversely affect NMJ transmission should be avoided, including ampicillin, aminoglycoside antibiotics, anti-arrhythmic agents, phenothiazines, anesthetics, narcotics, and muscle relaxants. Organophosphates may act in an additive manner with pyridostigmine; their concurrent use should therefore be avoided.

    7. Prognosis

      The overall prognosis for acquired MG in dogs is guarded due to this species’ propensity to develop megaesophagus and aspiration pneumonia. The prognosis for recovery from acquired MG in dogs is good if severe aspiration pneumonia or pharyngeal weakness is not present. In humans, the prognosis with uncomplicated acquired MG is considered good to excellent. However, the incidence of aspiration pneumonia in canine patients is significantly higher than in human medicine and the overall survival rate is therefore lower than human patients. The overall 1-yr mortality rate for canine acquired MG has been reported to be between 40 and 60%. The reason for death or euthanasia of myasthenic dogs is almost always severe or recurrent aspiration pneumonia. In order to maximize the chance of a favorable outcome in canine MG patients, aggressive prevention and/or treatment of aspiration pneumonia is essential. Anecdotally, the survival rate of dogs with acquired MG appears to have improved in recent years, perhaps due to the increased recognition and prompt diagnosis of the disorder, improved treatment options, or some combination of these two. In addition, there is evidence that the spontaneous remission of acquired MG in dogs is more common than previously thought. Some dogs (especially in the young age group) may go into spontaneous remission, even without immunosuppressive therapy. A retrospective study reported that 47/53 dogs treated with anticholinesterase therapy alone went into remission within an average of 6.4 mos.

         Information on documented cases of acquired MG in cats suggests that the prognosis for focal and generalized MG may be better than that reported for dogs. This is likely due to the lower incidence of megaesophagus and associated aspiration pneumonia in cats. In one series of acquired MG in 20 cats, only three of the cats died and all three of these presented with acute fulminating MG with death due to respiratory failure. Of the remaining cats, 11 of 20 demonstrated improvement of clinical signs at 2 mos after diagnosis, with six remaining unchanged. One-year follow-up was available for five cats, at which time two were still alive, while the other three cats had died or were euthanized for unrelated illnesses. At 1.5 yrs, two cats were found to be free of clinical signs of disease.

         Clinical remission of MG is associated with a return of serum ACh receptor antibody concentrations to the normal range. These concentrations should therefore be evaluated every 6–8 wks to monitor the clinical course of the disease.

Drugs and toxins associated with junctionopathies (Box 19.1 and Fig. 19.11)


Figure 19.11 Schematic representation of the pharmacology of the vertebrate neuromuscular junction. Many of the proteins that are involved in synaptic transmission at the mammalian neuromuscular junction are the targets of naturally occurring or synthetic drugs. The antagonists are shown as minus signs highlighted in red. The agonists are shown as plus signs highlighted in green. (Moczydlowski, 2011.192 Reprinted with permission.)

Apr 7, 2020 | Posted by in SMALL ANIMAL | Comments Off on Junctionopathies: Disorders of the Neuromuscular Junction
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